PROJECT SUMMARY/ABSTRACT Over the past decade, the success of deep brain stimulation (DBS) to treat motor diseases such as Parkinson's and dystonia has been extended in two directions: it is now being used to treat neuropsychiatric diseases in adults, such as obsessive-compulsive disorder, and Alzheimer's disease (AD), and it is beginning to be applied in children to treat both motor and neuropsychiatric diseases (dystonia and Tourette's, respectively). For example, a pilot study showed that forniceal stimulation in AD patients improves hippocampus-dependent memory tasks and slows cognitive decline, and in rodents, stimulation of the fimbria- fornix (FFx) or entorhinal cortex improves spatial memory, likely by modulating hippocampal theta-gamma oscillation, adult neurogenesis, or both. We have recently shown that forniceal DBS enhances hippocampal learning and memory as well as hippocampal synaptic plasticity and dentate neurogenesis in a mouse model of Rett Syndrome (RTT), the leading cause of intellectual disability in females. Caused mainly by mutations that impair the function of MeCP2, an epigenetic transcriptional modulator whose precise activities are the subject of intensive investigation, RTT manifests in females after the first year of life, causing profound cognitive impairment and a wide range of additional features. Affected children appear healthy at birth and achieve early developmental milestones, but between 12 and 18 months suddenly lose acquired motor, language, and social skills and develop an array of neurological and psychiatric features (hand stereotypies, anxiety, autistic behaviors, seizures, autonomic dysfunction, and motor deficits including dystonia, spasticity, and eventual parkinsonism). Several mouse models, either completely lacking MeCP2 or carrying hypofunctional alleles, reproduce the broad phenotype of the disorder, from early apparent health to regression and development of motor dysfunction, social and cognitive deficits; hippocampus-dependent learning and memory and hippocampal synaptic plasticity are impaired. We have shown that DBS rescues these hippocampal features, but the mechanism of action remains unclear: we hypothesize that multiple mechanisms (e.g., hippocampal neurogenesis, local field potential oscillations, hippocampal volume, and/or global neural network activity) might be at work. In this proposal we will (1) determine the extent of DBS effects, the duration of memory benefits, the optimal frequency of treatment, and effects in older animals; (2) investigate the possible mechanisms that contribute to the benefits in RTT mice; and (3) determine whether the memory benefits of forniceal DBS are generalizable to other mouse models of intellectual disability disorders. The data will provide insights into the value of manipulations at the circuit level and will hopefully lead to the design of new therapeutic approaches to RTT and other childhood disorders causing intellectual disability.